1. Technical Field
This document provides methods and materials related to using inhibitors of IL-9 signaling in conjunction with chemotherapy to treat cancer (e.g., solid tumors). For example, this document provides methods and materials for using inhibitors of IL-9 signaling (e.g., anti-IL9 antibody preparations) in conjunction with chemotherapy to treat cancer (e.g., solid tumors) or to reduce the growth rate of cancer (e.g., solid tumors) within a mammal.
2. Background Information
IL-9 is a paradoxical cytokine, as it mediates both pro-inflammatory events and tolerance induction. It is secreted by a host of pro-inflammatory immune cells including Th9 cells (Stassen et al., Ann. N Y Acad. Sci., 1247:56-68 (2012)), Th17 cells (Nowak and Noelle, Immunology, 131:169-73 (2010), CD8+ Tc9 cells (Visekruna et al., Eur. J. Immunol., 43:606-18 (2013)), eosinophils, mast cells, and innate lymphoid cells (Stassen et al., Ann. N YAcad. Sci., 1247:56-68 (2012), Goswami and Kaplan, J. Immunol., 186:3283-8 (2011), Jabeen and Kaplan, Curr. Opin. Immunol., 24:303-7 (2012), Noelle and Nowak, Nat. Rev. Immunol., 10:683-7 (2010), and Schmitt and Bopp, J. Clin. Invest., 122:3857-9 (2012)). It also is associated with tolerogenic cells such as T regulatory cells (Tregs). In this population IL-9 enhances Treg suppressive potency in an autocrine fashion (Elyaman et al., Proc. Natl. Acad. Sci. USA, 106:12885-90 (2009)), while promoting T cell tolerance via a paracrine impact upon mast cells (Eller et al., J. Immunol., 186:83-91 (2011), Lu et al., Nature, 442:997-1002 (2006), and Yang et al., PLoS ONE, 5:e8922 (2010)). This wide range of action is followed by an equally wide range of pathologies involving IL-9 secretion.
Most commonly IL-9 is linked to Th2 responses such as parasite expulsion and allergic airway inflammation, but it is also involved in autoimmunity and graft-versus-host disease (Noelle and Nowak, Nat. Rev. Immunol., 10:683-7 (2010)). IL-9 can be secreted by cells that promote opposite ends of the immune spectrum. For example: pro-inflammatory Th17 cells can produce IL-9 and exacerbate experimental autoimmune encephalitis (EAE) (Nowak et al., J. Exp. Med., 206:1653-60 (2009), whereas IL-9 secreted by Tregs renders them more suppressive and protects against EAE (Elyaman et al., Proc. Natl. Acad. Sci. USA, 106:12885-90 (2009)).
IL-9 also has seemingly contradictory roles in tumor biology. In some hematological tumors, the presence of IL-9 contributes to the establishment of a tolerogenic/immunosuppressive environment, or acts directly to drive tumor growth. IL-9 promotes the proliferation or survival of human lymphoid tumors such as Hodgkins lymphoma, acute lymphoblastic leukemia, myeloid leukemia, diffuse large B cell lymphoma, and NK T cell lymphoma (Merz et al., Blood, 78:1311-7 (1991), Lemoli et al., Blood, 87:3852-9 (1996), Lemoli et al., Leuk. Lymphoma, 26:563-73 (1997), Lv et al., Int. J. Clin. Exp. Pathol., 6:911-6 (2013), Lv and Wang, Leuk. Lymphoma, 54:1367-72 (2013) and Nagato et al., Clin. Cancer Res., 11:8250-7 (2005)). It also promotes the proliferation, migration and adhesion of human lung cancer cells (Matsushita et al., Leuk. Res., 21:211-6 (1997)).
IL-9, however, exhibits the opposite effect on melanoma biology in that it inhibits growth of B16 melanoma seeding in the lungs (Purwar et al., Nat. Med. 18:1248-53 (2012) and Lu et al., J. Clin. Invest., 122:4160-71 (2012)), through its effect directly on the lung epithelium, which then recruits dendritic cells.